In search for the fountain of youth, a lesson in doing good science

he study promised to be a big step toward cracking the code of aging: In 2000, scientists reported that giving roundworms a compound that blunted the effects of oxygen on their cells could boost their lifespans by 44 percent. After publishing their paper in Science, team leader Gordon Lithgow recalls, “We felt our work had moved the field on into seriously thinking about chemical slowing of aging.”

But soon after, they started getting phone calls from another lab. Researchers led by David Gems at University College London couldn’t get the same results, no matter what they tried. And in 2003, they published a paper saying so.

That dashing of hopes was “exceedingly disappointing,” Lithgow tells STAT.

advertisement

But the story has a happy ending, one that illustrates the way science works best. The experience jolted Lithgow to join with researchers around the United States to standardize testing of potential anti-aging compounds in roundworms. That project, known as the Caenorhabditis Intervention Testing Program (CITP), has led to its first results published this week: that, in carefully controlled side-by-side testing, most “fountain-of-youth” chemicals gave mixed results at best, but one drug did in fact extend the worms’ lifespan.

So what was going on? One possible answer was that “nothing works in Europe,” Lithgow told a laughing audience at a Buck Institute conference in August. “The other possible conclusion … is that we don’t really know what we’re doing here.”

So Lithgow’s lab at the Buck Institute in Novato, Calif., catalyzed the beginnings of the CITP, joining forces with a lab at Rutgers and another at the University of Oregon to test 21,000 worms from 22 strains, just to see whether their lifespans — untreated — were consistent.

They weren’t. The lifespans of roundworms turn out to vary greatly, even within labs. In fact, the largest variation was when the same researchers repeated experiments. Suddenly, it made sense that testing the same compound on what seemed like the same worms would lead to a different result: The worms weren’t identical after all.

Armed with that information, Lithgow and his colleagues started doing things differently, making sure they were working on the same strains of worm, and under the same conditions. They bought identical incubators, all from the same source. They worried about whether the heat from the lamps in their microscopes would affect results. “For quite a while, one of the three labs appeared to be an outlier with three days’ difference in lifespan,” Lithgow said. “Then one day on a conference call someone said, ‘Wait a minute, you call Day 1 the egg stage? We call Day 1 the first day of adulthood.’ That solved that particular mystery.”

And this week, in Nature Communications, they reported that they were able to extend lifespan consistently, in all strains, across all their various labs, with a compound called Thioflavin T.

That’s not to say that everything they tried worked. The other nine compounds they tested showed only uneven effects. And Lithgow noted that the group has had trouble publishing their findings, “but for understandable reasons. We do not provide any explanation (mechanism) for the variation we see nor do we test novel compounds (yet),” so peer reviewers were somewhat skeptical about accepting the paper.

But the lessons of this project are less about a particular anti-aging compound, and more about how to do reproducible science.

Courtesy of the CITP experience, Lithgow said, “I think we know a lot more about how to standardize experiments and to document what we are doing. We also know that building replication into the experiment (including multiple labs) helps a lot when trying to interpret the emerging data.”

That’s not the way most science is done now; replication tends to be seen as something that happens after publication, if it’s done at all. That’s changing, at least in some labs. And replication has taken more prominence in recent projects in psychology and cancer biology, albeit after publication.

As those projects are showing, then, the worms of science turn slowly — but they do turn.